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Daniel V. Santi - One of the best experts on this subject based on the ideXlab platform.
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long term stabilization of maleimide thiol conjugates
Bioconjugate Chemistry, 2015Co-Authors: Shaun D Fontaine, Ralph Reid, Gary W Ashley, Louise Robinson, Daniel V. SantiAbstract:Michael-addition of a thiol to a maleimide is commonly used for bioconjugation of drugs to macromolecules. Indeed, both current FDA-approved antibody–drug conjugates—Brentuximab vedotin and Trastuzumab emtansine—and one approved PEGylated conjugate—Cimzia—contain a thiol–maleimide adduct. However, the ultimate in vivo fate of such adducts is to undergo disruptive cleavage by thiol exchange or stabilizing ring opening. Therapeutic efficacy of a conjugate can be compromised by thiol exchange and the released drug may show toxicities. However, if the succinimide moiety of a maleimide–thiol conjugate is hydrolyzed, the ring-opened product is stabilized toward cleavage. We determined rates of ring-opening hydrolysis and thiol exchange of a series of N-substituted succinimide thioethers formed by maleimide–thiol conjugation. Ring-opening of conjugates prepared with commonly used Maleimides were too slow to serve as prevention against thiol exchange. However, ring-opening rates are greatly accelerated by electro...
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Long-term stabilization of maleimide-thiol conjugates
Bioconjugate Chemistry, 2015Co-Authors: Shaun D Fontaine, Ralph Reid, Gary W Ashley, Louise Robinson, Daniel V. SantiAbstract:Michael-addition of a thiol to a maleimide is commonly used for bioconjugation of drugs to macromolecules. Indeed, both current FDA-approved antibody-drug conjugates-Brentuximab vedotin and Trastuzumab emtansine-and one approved PEGylated conjugate-Cimzia-contain a thiol-maleimide adduct. However, the ultimate in vivo fate of such adducts is to undergo disruptive cleavage by thiol exchange or stabilizing ring opening. Therapeutic efficacy of a conjugate can be compromised by thiol exchange and the released drug may show toxicities. However, if the succinimide moiety of a maleimide-thiol conjugate is hydrolyzed, the ring-opened product is stabilized toward cleavage. We determined rates of ring-opening hydrolysis and thiol exchange of a series of N-substituted succinimide thioethers formed by maleimide-thiol conjugation. Ring-opening of conjugates prepared with commonly used Maleimides were too slow to serve as prevention against thiol exchange. However, ring-opening rates are greatly accelerated by electron withdrawing N-substituents, and ring-opened products have half-lives of over two years. Thus, conjugates made with electron-withdrawing Maleimides may be purposefully hydrolyzed to their ring-opened counterparts in vitro to ensure in vivo stability.
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Long-Term Stabilization of Maleimide–Thiol Conjugates
Bioconjugate Chemistry, 2014Co-Authors: Shaun D Fontaine, Ralph Reid, Gary W Ashley, Louise Robinson, Daniel V. SantiAbstract:Michael-addition of a thiol to a maleimide is commonly used for bioconjugation of drugs to macromolecules. Indeed, both current FDA-approved antibody–drug conjugates—Brentuximab vedotin and Trastuzumab emtansine—and one approved PEGylated conjugate—Cimzia—contain a thiol–maleimide adduct. However, the ultimate in vivo fate of such adducts is to undergo disruptive cleavage by thiol exchange or stabilizing ring opening. Therapeutic efficacy of a conjugate can be compromised by thiol exchange and the released drug may show toxicities. However, if the succinimide moiety of a maleimide–thiol conjugate is hydrolyzed, the ring-opened product is stabilized toward cleavage. We determined rates of ring-opening hydrolysis and thiol exchange of a series of N-substituted succinimide thioethers formed by maleimide–thiol conjugation. Ring-opening of conjugates prepared with commonly used Maleimides were too slow to serve as prevention against thiol exchange. However, ring-opening rates are greatly accelerated by electro...
Maria N. Preobrazhenskaya - One of the best experts on this subject based on the ideXlab platform.
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macrolactones built from the bis 3 4 indol 1 yl maleimide scaffold
Tetrahedron, 2014Co-Authors: Alexander Y Simonov, Sergey A Lakatosh, E E Bykov, M. I. Reznikova, Yuri N Luzikov, A. M. Korolev, Maria N. PreobrazhenskayaAbstract:Abstract 15, 16, and 17-Membered lactones based on the bis-3,4(indol-1-yl)maleimide framework were obtained using intramolecular esterification reaction starting from 3-(1-ω-carboxyalkyl-2,3-dihydroindol-1-yl)-4-(1-ω-hydroxyalkyl-2,3-dihydroindol-1-yl)-Maleimides. 3,4-Dibromo-maleimide, ω-(2,3-dihydroindol-3-yl)alkanoic acids, and ω-(2,3-dihydroindol-3-yl)alkanoles were used as starting compounds. Substitution of Br for the substituted indolines followed by the intramolecular cyclization of O-silylated hydroxyl acids derivatives led to macrolactones that incorporated 4-(dihydroindol-1-yl)-3-(indol-1-yl)maleimide moieties. Indoline nuclei in these compounds were dehydrogenated by DDQ in refluxing toluene to give 15, 16 or 17-membered lactones 3-[(ω-3-carboxyalkylindol-1-yl)-4-(ω-hydroxyalkylindol-1-yl)Maleimides. Quantum chemical calculations showed that the formation of macrolactones of smaller size (13-membered) corresponds to the higher Gibbs energy ΔG# and correlates with the absence of the target reaction product.
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synthesis of 4 substituted 3 3 dialkylaminomethyl indol 1 yl Maleimides and study of their ability to inhibit protein kinase c α prevent development of multiple drug resistance of tumor cells and cytotoxicity
Russian Chemical Bulletin, 2008Co-Authors: Yu A Simonov, Sergey A Lakatosh, M. I. Reznikova, Yuri N Luzikov, Yu O Susova, Alexander A Shtil, S M Elizarov, Valery N Danilenko, Maria N. PreobrazhenskayaAbstract:A series of 3-[3-(dialkylaminomethyl)indol-1-yl]Maleimides containing the indole, dihydroindole, mercaptophenol, or tetrahydroquinoline residues at position 4 of the maleimide ring, as well as 3-(dialkylaminomethyl)indole derivatives have been synthesized. Their ability to inhibit in vitro protein kinase C-α (PKC-α) has been studied. Cytotoxicity of new compounds and their ability to constrain activation of multiple drug resistance (MDR) have been studied in the human tumor cell line. Both the toxic and the low-toxic PKC-α inhibitors prevent the activation of MDR in the tumor cells. Among compounds under study, a number of substances have been found that prevent the activation of MDR but do not inhibit PKC-α.
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synthesis of 6h pyrrolo 3 4 2 3 1 4 diazepino 6 7 1 hi indole 8 10 7h 9h diones using 3 bromo 4 indol 1 yl maleimide scaffold
Organic and Biomolecular Chemistry, 2003Co-Authors: Sergey A Lakatosh, Yuri N Luzikov, Maria N. PreobrazhenskayaAbstract:Series of 3-arylalkyl- or 3-alkylamino-4-(indol-1-yl)Maleimides and bis(indol-1-yl)Maleimides were synthesised. The cyclization of the 3-substituted 4-(indol-1-yl)Maleimides under the action of acids resulted in the formation of diazepine[1,4] derivatives with indoline and maleimide nuclei annelated. These compounds readily produced the corresponding indolomaleimidodiazepines[1,4] after dehydrogenation.
Anna Grandas - One of the best experts on this subject based on the ideXlab platform.
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Exploiting Protected Maleimides to Modify Oligonucleotides, Peptides and Peptide Nucleic Acids
Molecules, 2015Co-Authors: Clément Paris, Omar Brun, Enrique Pedroso, Anna GrandasAbstract:This manuscript reviews the possibilities offered by 2,5-dimethylfuran-protected Maleimides. Suitably derivatized building blocks incorporating the exo Diels-Alder cycloadduct can be introduced at any position of oligonucleotides, peptide nucleic acids, peptides and peptoids, making use of standard solid-phase procedures. Maleimide deprotection takes place upon heating, which can be followed by either Michael-type or Diels-Alder click conjugation reactions. However, the one-pot procedure in which maleimide deprotection and conjugation are simultaneously carried out provides the target conjugate more quickly and, more importantly, in better yield. This procedure is compatible with conjugates involving oligonucleotides, peptides and peptide nucleic acids. A variety of cyclic peptides and oligonucleotides can be obtained from peptide and oligonucleotide precursors incorporating protected Maleimides and thiols.
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Protected maleimide building blocks for the decoration of peptides, peptoids, and peptide nucleic acids.
Bioconjugate chemistry, 2013Co-Authors: Xavier Elduque, Enrique Pedroso, Albert Sanchez, Kapil Sharma, Anna GrandasAbstract:Monomers allowing for the introduction of [2,5-dimethylfuran]-protected Maleimides into polyamides such as peptides, peptide nucleic acids, and peptoids were prepared, as well as the corresponding oligomers. Suitable maleimide deprotection conditions were established in each case. The stability of the adducts generated by Michael-type maleimide–thiol reaction and Diels–Alder cycloaddition to maleimide deprotection conditions was exploited to prepare a variety of conjugates from peptide and PNA scaffolds incorporating one free and one protected maleimide. The target molecules were synthesized by using two subsequent maleimide-involving click reactions separated by a maleimide deprotection step. Carrying out maleimide deprotection and conjugation simultaneously gave better results than performing the two reactions subsequently.
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Conjugation Reactions Involving Maleimides and Phosphorothioate Oligonucleotides
Bioconjugate Chemistry, 2012Co-Authors: Albert Sanchez, Enrique Pedroso, Anna GrandasAbstract:Phosphorothioate diester oligonucleotides proved to be fully compatible with Maleimides in the context of two different conjugation reactions: (a) reaction of 5′diene-[phosphorothioate oligonucleotides] with maleimido-containing compounds to afford the Diels–Alder cycloadduct; (b) conjugation of 5′maleimido-[phosphorothioate oligonucleotides] with thiol-containing compounds. No evidence of reaction between phosphorothioate diesters and Maleimides was found in any of these processes. Importantly, in the preparation of 5′maleimido-[phosphorothioate oligonucleotides] from [protected maleimido]-[phosphorothioate oligonucleotides], which requires the maleimide to be deprotected by retro-Diels–Alder reaction (heating for 3–4 h in toluene at 90 °C), no addition of phosphorothioate diester to the maleimide was found either. Finally, maleimide-[phosphorothioate monoester] conjugation was also explored for comparison purposes.
Shaun D Fontaine - One of the best experts on this subject based on the ideXlab platform.
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long term stabilization of maleimide thiol conjugates
Bioconjugate Chemistry, 2015Co-Authors: Shaun D Fontaine, Ralph Reid, Gary W Ashley, Louise Robinson, Daniel V. SantiAbstract:Michael-addition of a thiol to a maleimide is commonly used for bioconjugation of drugs to macromolecules. Indeed, both current FDA-approved antibody–drug conjugates—Brentuximab vedotin and Trastuzumab emtansine—and one approved PEGylated conjugate—Cimzia—contain a thiol–maleimide adduct. However, the ultimate in vivo fate of such adducts is to undergo disruptive cleavage by thiol exchange or stabilizing ring opening. Therapeutic efficacy of a conjugate can be compromised by thiol exchange and the released drug may show toxicities. However, if the succinimide moiety of a maleimide–thiol conjugate is hydrolyzed, the ring-opened product is stabilized toward cleavage. We determined rates of ring-opening hydrolysis and thiol exchange of a series of N-substituted succinimide thioethers formed by maleimide–thiol conjugation. Ring-opening of conjugates prepared with commonly used Maleimides were too slow to serve as prevention against thiol exchange. However, ring-opening rates are greatly accelerated by electro...
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Long-term stabilization of maleimide-thiol conjugates
Bioconjugate Chemistry, 2015Co-Authors: Shaun D Fontaine, Ralph Reid, Gary W Ashley, Louise Robinson, Daniel V. SantiAbstract:Michael-addition of a thiol to a maleimide is commonly used for bioconjugation of drugs to macromolecules. Indeed, both current FDA-approved antibody-drug conjugates-Brentuximab vedotin and Trastuzumab emtansine-and one approved PEGylated conjugate-Cimzia-contain a thiol-maleimide adduct. However, the ultimate in vivo fate of such adducts is to undergo disruptive cleavage by thiol exchange or stabilizing ring opening. Therapeutic efficacy of a conjugate can be compromised by thiol exchange and the released drug may show toxicities. However, if the succinimide moiety of a maleimide-thiol conjugate is hydrolyzed, the ring-opened product is stabilized toward cleavage. We determined rates of ring-opening hydrolysis and thiol exchange of a series of N-substituted succinimide thioethers formed by maleimide-thiol conjugation. Ring-opening of conjugates prepared with commonly used Maleimides were too slow to serve as prevention against thiol exchange. However, ring-opening rates are greatly accelerated by electron withdrawing N-substituents, and ring-opened products have half-lives of over two years. Thus, conjugates made with electron-withdrawing Maleimides may be purposefully hydrolyzed to their ring-opened counterparts in vitro to ensure in vivo stability.
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Long-Term Stabilization of Maleimide–Thiol Conjugates
Bioconjugate Chemistry, 2014Co-Authors: Shaun D Fontaine, Ralph Reid, Gary W Ashley, Louise Robinson, Daniel V. SantiAbstract:Michael-addition of a thiol to a maleimide is commonly used for bioconjugation of drugs to macromolecules. Indeed, both current FDA-approved antibody–drug conjugates—Brentuximab vedotin and Trastuzumab emtansine—and one approved PEGylated conjugate—Cimzia—contain a thiol–maleimide adduct. However, the ultimate in vivo fate of such adducts is to undergo disruptive cleavage by thiol exchange or stabilizing ring opening. Therapeutic efficacy of a conjugate can be compromised by thiol exchange and the released drug may show toxicities. However, if the succinimide moiety of a maleimide–thiol conjugate is hydrolyzed, the ring-opened product is stabilized toward cleavage. We determined rates of ring-opening hydrolysis and thiol exchange of a series of N-substituted succinimide thioethers formed by maleimide–thiol conjugation. Ring-opening of conjugates prepared with commonly used Maleimides were too slow to serve as prevention against thiol exchange. However, ring-opening rates are greatly accelerated by electro...
Sergey A Lakatosh - One of the best experts on this subject based on the ideXlab platform.
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3,4-Disubstituted Maleimides: synthesis and biological activity
Chemistry of Heterocyclic Compounds, 2018Co-Authors: Aleksandrovich Aleksej Panov, Sergey A Lakatosh, Alexander Y Simonov, Sergey N. Lavrenov, Andreevich Stanislav TreninAbstract:This review is devoted to methods for the synthesis of 3,4-disubstituted Maleimides – compounds that often show pronounced biological activity. We offer classification of synthetic methods, present comparative analysis of various approaches while describing their advantages and drawbacks. The areas of practical applications are indicated for several 3,4-disubstituted maleimide derivatives in the role of pharmaceutical agents or reactive dyes. The majority of the considered publications are from the last 10 years.
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macrolactones built from the bis 3 4 indol 1 yl maleimide scaffold
Tetrahedron, 2014Co-Authors: Alexander Y Simonov, Sergey A Lakatosh, E E Bykov, M. I. Reznikova, Yuri N Luzikov, A. M. Korolev, Maria N. PreobrazhenskayaAbstract:Abstract 15, 16, and 17-Membered lactones based on the bis-3,4(indol-1-yl)maleimide framework were obtained using intramolecular esterification reaction starting from 3-(1-ω-carboxyalkyl-2,3-dihydroindol-1-yl)-4-(1-ω-hydroxyalkyl-2,3-dihydroindol-1-yl)-Maleimides. 3,4-Dibromo-maleimide, ω-(2,3-dihydroindol-3-yl)alkanoic acids, and ω-(2,3-dihydroindol-3-yl)alkanoles were used as starting compounds. Substitution of Br for the substituted indolines followed by the intramolecular cyclization of O-silylated hydroxyl acids derivatives led to macrolactones that incorporated 4-(dihydroindol-1-yl)-3-(indol-1-yl)maleimide moieties. Indoline nuclei in these compounds were dehydrogenated by DDQ in refluxing toluene to give 15, 16 or 17-membered lactones 3-[(ω-3-carboxyalkylindol-1-yl)-4-(ω-hydroxyalkylindol-1-yl)Maleimides. Quantum chemical calculations showed that the formation of macrolactones of smaller size (13-membered) corresponds to the higher Gibbs energy ΔG# and correlates with the absence of the target reaction product.
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synthesis of 4 substituted 3 3 dialkylaminomethyl indol 1 yl Maleimides and study of their ability to inhibit protein kinase c α prevent development of multiple drug resistance of tumor cells and cytotoxicity
Russian Chemical Bulletin, 2008Co-Authors: Yu A Simonov, Sergey A Lakatosh, M. I. Reznikova, Yuri N Luzikov, Yu O Susova, Alexander A Shtil, S M Elizarov, Valery N Danilenko, Maria N. PreobrazhenskayaAbstract:A series of 3-[3-(dialkylaminomethyl)indol-1-yl]Maleimides containing the indole, dihydroindole, mercaptophenol, or tetrahydroquinoline residues at position 4 of the maleimide ring, as well as 3-(dialkylaminomethyl)indole derivatives have been synthesized. Their ability to inhibit in vitro protein kinase C-α (PKC-α) has been studied. Cytotoxicity of new compounds and their ability to constrain activation of multiple drug resistance (MDR) have been studied in the human tumor cell line. Both the toxic and the low-toxic PKC-α inhibitors prevent the activation of MDR in the tumor cells. Among compounds under study, a number of substances have been found that prevent the activation of MDR but do not inhibit PKC-α.
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synthesis of 6h pyrrolo 3 4 2 3 1 4 diazepino 6 7 1 hi indole 8 10 7h 9h diones using 3 bromo 4 indol 1 yl maleimide scaffold
Organic and Biomolecular Chemistry, 2003Co-Authors: Sergey A Lakatosh, Yuri N Luzikov, Maria N. PreobrazhenskayaAbstract:Series of 3-arylalkyl- or 3-alkylamino-4-(indol-1-yl)Maleimides and bis(indol-1-yl)Maleimides were synthesised. The cyclization of the 3-substituted 4-(indol-1-yl)Maleimides under the action of acids resulted in the formation of diazepine[1,4] derivatives with indoline and maleimide nuclei annelated. These compounds readily produced the corresponding indolomaleimidodiazepines[1,4] after dehydrogenation.
